Interpretive Summary: Pterostilbene, a naturally occurring phenolic compound produced by plants of the Genera Vitis and Vaccinium, among others, has been shown to possess diverse pharmacological properties, including lipid- and glucose-lowering, and cancer-chemopreventive activity. It is also considered to be a phytoalexin that exhibits strong antifungal activity. The aim of the present study was to investigate the whole genomic response of yeast cells exposed to pterostilbene using DNA microarray technology. Results from a genome-wide gene expression analysis showed that ~18% of the genes represented on the Affymetrix S98 yeast arrays were significantly induced or repressed when yeast cells were treated with pterostilbene. The gene ontology-based analyses showed that pterostilbene exposure significantly down-regulated the expression of genes involved in methionine metabolism, while the expression of genes involved in mitochondrial functions, response to drug exposure, and transcription factor activity were significantly up-regulated. Additional analysis revealed that pterostilbene has a significant effect on methionine metabolism, a previously unreported effect for this compound.

Technical Abstract:
Pterostilbene, a naturally occurring phenolic compound produced by agronomically important plant genera such as Vitis and Vacciunium, is a phytoalexin exhibiting potent antifungal activity. Additionally, recent studies have demonstrated several important pharmacological properties associated with pterostilbene. Despite this, a systematic study of the effects of pterostilbene on eukaryotic cells at the molecular level has not been previously reported. Thus, the aim of the present study was to identify the cellular pathways affected by pterostilbene by performing transcript profiling studies, employing in the model yeast Saccharomyces cerevisiae. Yeast strain S288C was exposed to pterostilebene at the IC50 concentration (70 uM) for one generation (3 h). Transcript profiling experiments were performed on three biological replicate samples using the Affymetrix GeneChip Yeast Genome S98 Array. The data were analyzed using the statistical methods available in the GeneSifter microarray data analysis system. To validate the results, eleven differentially expressed genes were further examined by quantitative real-time RT-PCR, and S. cerevisiae mutant strains with deletions in these genes were analyzed for altered sensitivity to pterostilbene. The present studies revealed that pterostilbene exposure significantly down-regulated the expression of genes involved in methionine metabolism, while the expression of genes involved in mitochondrial functions, drug detoxification, and transcription factor activity were significantly up-regulated. Additional analyses revealed that a large number of genes involved in lipid metabolism were also affected by pterostilbene treatment. The observed response in lipid metabolism genes is consistent with its known hypolipidemic properties. Furthermore, the induction of mitochondrial genes is in agreement with the recent reports that pterostilbene-induced apoptosis is associated with the mitochondrial pathway in human cancer cell lines.